Summary In contrast to conventional T cells that recognize peptides on MHC proteins, CD1 molecules present lipid antigens to T lymphocytes. The abundant expression of CD1a hallmarks Langerhans cells in the skin, a subtype of dendritic cell with antigen-presenting functions. CD1a is able to bind and display a broad spectrum of lipid antigens derived from exogenous sources, such as bacteria, or host origin. The complex immune system of the skin is critically involved in responses to extrinsic insults like allergens, as well as in autoimmune diseases, such as psoriasis. However, the in vivo role of CD1a on Langerhans cells remains enigmatic, since CD1a is expressed in humans but lacking in most animal models. Our hypothesis is that CD1a on Langerhans cells is critical to control inflammatory skin diseases. We will support this hypothesis with the following specific aims: 1) Investigate the impact of CD1a on inflammatory skin diseases. To overcome the obstacle of CD1a lacking in normal experimental animals, we propose to use human CD1a-transgenic mice to study the impact of CD1a on skin inflammation. We show that the lipidic substance urushiol from the plant poison ivy induces severe skin inflammation in a CD1a-dependent fashion. The immune response is exclusively driven by CD1a-expressing Langerhans cells that elicit the generation of CD4 T cells, producing the inflammatory cytokines IL-17 and IL- 22. In a model for psoriasis, CD1a massively amplifies inflammation mediated by Th17 cells reactive with self lipid antigens from skin. Strikingly, treatment with blocking antibodies against CD1a fully abrogates skin inflammation. These experiments will provide the first in vivo evidence that CD1a on Langerhans cells is essential to control skin inflammation. 2) Elucidate the mechanism of lipid presentation and recognition in skin inflammation. For this purpose, we will analyze antigen specificity (TCR repertoire) of CD1a-restricted T cells. We plan to generate new tools such as CD1a tetramers and novel techniques for lipid loading of CD1a molecules. Further, we will develop new kinetic measurements for binding of lipids to CD1a. Using structural biology, we resolve the crystal structure of the CD1a/urushiol complex. This forms the basis for subsequent structural studies on the ternary complex between TCR and lipids presented by CD1a, and will also help to identify dominant lipid antigens in inflammatory skin diseases. Finally, we translate our findings to the human system and demonstrate that poison ivy responders and patients suffering from psoriasis show strong inflammatory T cell activation in response to CD1a. Taken together, we propose CD1a as a novel target for future therapeutic strategies against inflammatory skin diseases.